Multicomponent Ligation of Steroids: Creating Diversity at the Linkage Moiety of Bis-spirostanic Conjugates by Ugi Reactions

The diversity-oriented synthesis of novel bis-spirostanic conjugates utilizing two different Ugi four-component reactions (Ugi-4CR) is described. Spirostanic steroids were functionalized with Ugi-reactive groups, that is, amines, isocyanides, and carboxylic acids, and next were subjected to multicomponent ligation approaches leading to bis-steroidal conjugates featuring pseudo-peptidic and heterocyclic linkage moieties. Both the classic Ugi-4CR and its hydrazoic acid variant were implemented, proving good efficiency for the ligation of isocyanosteroids to spirostanic acids and equatorial amines. Axially oriented amines showed poorer results, although model studies proved that chemical efficiency could be significantly improved while increasing reaction times. Overall, the method comprises the rapid generation of molecular diversity at the bis-steroid linkage moiety and, consequently, shows promise toward the production of combinatorial libraries of bis-spirostanes for biological screening.

Pérez-Labrada, Karell; Méndez, Yanira; Brouard, Ignacio; Rivera, Daniel G.

ACS Combinatorial Science 15(6): 320-330 (2013)
DOIDigital.CSIC

A Novel Approach for the Evaluation of Positive Cooperative Guest Binding: Kinetic Consequences of Structural Tightening

Cooperativity is one of the most relevant features displayed by biomolecules. Thus, one of the challenges in the field of supramolecular chemistry is to understand the mechanisms underlying cooperative binding effects. Traditionally, cooperativity has been related to multivalent receptors, but Williams et al. have proposed a different interpretation based on the strengthening of noncovalent interactions within receptors upon binding. According to such an interpretation, positive cooperative binding operates through structural tightening. Hence, a quite counterintuitive kinetic behavior for positively cooperative bound complexes may be postulated: the more stable the complex, the slower it is formed. Such a hypothesis was tested in a synthetic system in which positive cooperative binding was previously confirmed by calorimetric experiments. Indeed, a linear correlation between the thermodynamics (ΔG°) and the kinetics (ΔG≠) of guest binding confirmed the expected behavior. These distinctive kinetics provide solid evidence of positive cooperative guest binding, which is particularly useful bearing in mind that kinetic experiments are frequently and accurately carried out in both synthetic and biological systems.

Carrillo Fumero, Romen; Morales, E. ; Martín, Víctor S.; Martín, Tomás

Chemistry-A European Journal 19: 7042-7048 (2013)
DOIDigital.CSIC

Epoxide-opening cascades triggered by a Nicholas reaction: Total synthesis of teurilene

Natural inspiration: Based on the biosynthesis of squalene‐derived polyethers, a total synthesis of teurilene is described. The carbocation formation in the Nicholas reaction serves to control the initiation of a polyepoxide ring‐opening cascade. The three furan rings present in teurilene were obtained in excellent yield in one step. Boc=tert‐butoxycarbonyl, TMS=trimethylsilyl.

Rodríguez-López, Julio; Pinacho Crisóstomo, Fernando R.; Ortega, Nuria; López Rodríguez, Matías; Martín, Víctor S.; Martín, Tomás

Angewandte Chemie - International Edition 52(13): 3659-3662 (2013)
DOIDigital.CSIC

Synthesis of Chiral β-Iodo- and Vinylorganophosphorus(V) Compounds by Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals

A new general methodology for the synthesis of chiral vinylphosphonate and vinylphosphine oxide carbohydrate derivatives has been developed using the anomeric alkoxyl radical fragmentation reaction as the key step. The synthetic sequence proceeded via β-iodophosphonate and β-iodophosphine oxide intermediates, which may be interesting synthons for the introduction of phosphorus into organic molecules. These vinylphosphonates could be easily transformed into 2-methylene-1-phosphapentofuranoses (3-methylene-1,2-oxaphospholanes) and β-aminophosphonates, isosteres of biologically active α-methylene-γ-lactones and β-amino acids, respectively.

Hernández-Guerra, Daniel; Rodríguez Morales, María S.; Suárez, Ernesto

Organic Letters 15(2): 250-253 (2013)
DOIDigital.CSIC

Iron(III) Catalyzed Direct Synthesis of cis-2,7-Disubstituted Oxepanes. The Shortest Total Synthesis of (+)-Isolaurepan

Prins cyclization of bis-homoallylic alcohols with aldehydes catalyzed by iron(III) salts shows excellent cis selectivity and yields to form 2,7-disubstituted oxepanes. The iron(III) is able to catalyze this process with unactivated olefins. This cyclization was used as the key step in the shortest total synthesis of (+)-isolaurepan.

Purino, Martín A.; Ramírez, Miguel A.; Daranas, Antonio: Martín, Víctor; Padrón, Juan I.

Organic Letteer 14(23): 5904-5907 (2012)
DOI

Conformation and Chiral Effects in α,β,α-Tripeptides

Short α,β,α-tripeptides comprising a central chiral trisubstituted β2,2,3*-amino acid residue form unusual γ-turns and δ-turns in CDCl3 and DMSO-d6 solutions but do not form β-turns. Thermal coefficients of backbone amide protons, 2D-NMR spectra, and molecular modeling revealed that these motifs were strongly dependent on the configuration (chiral effect) of the central β-amino acid residue within the triad. Accordingly, SSS tripeptides adopted an intraresidual γ-turn like (C6) arrangement in the central β-amino acid, whereas SRS diastereomers preferred an extended δ-turn (C9) conformation. A different SRS-stabilizing bias was observed in the crystal structures of the same compounds, which shared the extended δ-turn (C9) found in solution, but incorporated an additional extended β-turn (C11) to form an overlapped double turn motif.

Saavedra, Carlos J.; Boto, Alicia; Hernández, Rosendo; Miranda, José Ignacio; Aizpurua, Jesus M.

J. Org. Chem. 77(14): 5907-5913 ( 2012)
DOI

Synthesis of α,γ-peptide hybrids by selective conversion of glutamic acid units

The site-selective modification of small peptides at a glutamate residue allows the ready preparation of α,γ-hybrids. In this way, a single peptide can be transformed into a variety of hybrid derivatives. The process takes place under very mild conditions, and good global yields are obtained.

Saavedra, Carlos J.; Boto, Alicia; Hernández, Rosendo

Organic Letters 14(13): 3542-3545 (2012)
DOIDigital.CSIC

Synthesis of α,γ-peptide hybrids by selective conversion of glutamic acid units

The site-selective modification of small peptides at a glutamate residue allows the ready preparation of α,γ-hybrids. In this way, a single peptide can be transformed into a variety of hybrid derivatives. The process takes place under very mild conditions, and good global yields are obtained.

Saavedra, Carlos J.; Boto, Alicia; Hernández, Rosendo

Organic Letters 14(13): 3542-3545 (2012)
DOIDigital.CSIC

Towards a Structural Basis for the Relationship Between Blood Group and the Severity of El Tor Cholera

It has long been known that people with blood group O are more severely affected by El Tor cholera than those with blood groups A or B. Microcalorimetry and NMR spectroscopy are used to evaluate the ability of the B‐subunits of cholera toxin and E. coli heat‐labile toxin to bind to selected blood group oligosaccharides.

Mandal, Pintu K.; Branson, Thomas R.; Hayes, Edward D.; Ross, James F.; Gavín, José A.; Hernández Daranas, Antonio; Turnbull, W. Bruce

Angewandte Chemie - International Edition 51(21): 5143-5146 (2012)
DOIDigital.CSIC

Major components of Spanish cultivated Artemisia absinthium populations: Antifeedant, antiparasitic, and antioxidant effects

The objective of this study was the valorization of Spanish Artemisia absinthium populations from Teruel (Aragón) and Sierra Nevada (Granada). These populations were experimentally cultivated in the field and under controlled conditions. Three major components were isolated from a two year-old population obtained from the Teruel population cultivated in Ejea-Zaragoza in 2003, and identified by NMR experiments as the sequiterpene lactone hydroxypelenolide (I) and the flavones artemetin (II) and casticin (III). The I–III content of the plant extracts was analyzed by HPLC-DAD. The insect antifeedant properties of plant extracts from different years and crops were tested against Spodoptera littoralis, Myzus persicae and Rhopalosiphum padi. Additionally we studied their antioxidant, phytotoxic and antiparasitic effects.

Gonzalez-Coloma, Azucena; Bailen, Maria; Diaz, Carmen E.; Fraga, Braulio M.; Martínez-Díaz, Rafael; Zuñiga, Gustavo E.; Contreras, Rodrigo A.; Cabrera, Raimundo; Burillo, Jesus

Industrial Crops and Products 37(1): 401-407 (2012)
DOI